EP1490043A2 - Amides spirocycliques en tant que modulateurs du recepteur cannabinoide - Google Patents

Amides spirocycliques en tant que modulateurs du recepteur cannabinoide

Info

Publication number
EP1490043A2
EP1490043A2 EP03711667A EP03711667A EP1490043A2 EP 1490043 A2 EP1490043 A2 EP 1490043A2 EP 03711667 A EP03711667 A EP 03711667A EP 03711667 A EP03711667 A EP 03711667A EP 1490043 A2 EP1490043 A2 EP 1490043A2
Authority
EP
European Patent Office
Prior art keywords
chlorophenyl
methylpropyl
cyanophenyl
bis
cyclopentanecarboxamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03711667A
Other languages
German (de)
English (en)
Other versions
EP1490043A4 (fr
Inventor
William K. Hagmann
Linus S. Lin
Shrenik K. Shah
Mark T. Goulet
James P. Jewell
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme LLC
Original Assignee
Merck and Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP1490043A2 publication Critical patent/EP1490043A2/fr
Publication of EP1490043A4 publication Critical patent/EP1490043A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/38—2-Pyrrolones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/59—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/82—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • Marijuana (Cannabis sativa L.) and its derivatives have been used for centuries for medicinal and recreational purposes.
  • a major active ingredient in marijuana and hashish has been determined to be ⁇ 9-tetrahydrocannabinol ( ⁇ 9-THC).
  • ⁇ 9-THC ⁇ 9-tetrahydrocannabinol
  • CBl and CB2 G-protein coupled receptors
  • the CBl receptor is primarily found in the central and peripheral nervous systems and to a lesser extent in several peripheral organs.
  • the CB2 receptor is found primarily in lymphoid tissues and cells.
  • mice The genes for the respective cannabinoid receptors have each been disrupted in mice.
  • the CBl-/- receptor knockout mice appeared normal and fertile. They were resistant to the effects of ⁇ 9-THC and demonstrated a strong reduction in the reinforcing properties of morphine and the severity of withdrawal syndrome. They also demonstrated reduced motor activity and hypoalgesia.
  • the CB2-/- receptor knockout mice were also healthy and fertile. They were not resistant to the central nervous system mediated effects of administered ⁇ 9-THC. There were some effects on immune cell activation, reinforcing the role for the CB2 receptor in immune system functions. Excessive exposure to ⁇ 9-THC can lead to overeating, psychosis, hypothermia, memory loss, and sedation.
  • CBl receptor modulators such as CBl inverse agonists
  • CBl inverse agonists Treatment of asthma with CBl receptor modulators is supported by the finding that presynaptic cannabinoid CBl receptors mediate the inhibition of noradrenaline release (in the guinea pig lung) (Europ. J. of Pharmacology, 2001, 431 (2), 237-244).
  • Treatment of cirrhosis of the liver with CB 1 receptor modulators is supported by the finding that a CBl receptor modulator will reverse the low blood pressure observed in rats with carbon tetrachloride-induced liver cirrhosis and will lower the elevated mesenteric blood flow and portal vein pressure (Nature Medicine, 2001, 7 (7), 827-832).
  • US Patent US 5,532,237 discloses N-benzoyl-indole derivatives having activity against the cannabinoid receptors.
  • US Patents US 4,973,587, US 5,013,837, US 5,081,122, and US 5,112,820, US 5,292,736 disclose aminoalkylindole derivatives as having activity against the cannabinoid receptors.
  • PCT publication WO 01/58869 discloses pyrazoles, pyrroles and imidazole cannabinoid receptor modulators useful for treating respiratory and non- respiratory leukocyte activation-associated disorders.
  • Bl, B2 and Ri are hydrogen, R2 is aryl or heteroaryl, m is 1 and L is C3-7cycloalkyl; and their use as neuropeptide Y Y5 receptor ligands for the treatment of obesity and other disorders associated with NPY receptor subtype Y5.
  • R ⁇ is hydrogen or lower alkyl
  • R a and R6b are hydrogen
  • Y is a single bond
  • R3 and R4 are phenyl
  • Rl is H, methyl or ethyl
  • R2 is phenyl
  • X is -CH2-
  • Z is phenyl
  • the compounds of the present invention are modulators of the Cannabinoid-1 (CBl) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the Cannabinoid-1 (CBl) receptor.
  • compounds of the present invention are antagonists or inverse agonists of the CBl receptor.
  • the invention is concerned with the use of these compounds to modulate the Cannabinoid-1 (CBl) receptor.
  • compounds of the present invention are useful as psychotropic drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia.
  • the compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, marijuana, and nicotine.
  • the compounds are also useful for the treatment of eating disorders by inhibiting excessive food intake and the resulting obesity and complications associated therewith.
  • the compounds are also useful for the treatment of constipation and chronic intestinal pseudo-obstruction, as well as for the treatment of asthma, and cirrhosis of the liver.
  • the present invention is concerned with substituted amides of the general Formula I:
  • (I) and pharmaceutically acceptable salts thereof which are antagonists and/or inverse agonists of the Cannabinoid-1 (CBl) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the Cannabinoid-1 (CBl) receptor.
  • the invention is concerned with the use of these novel compounds to selectively antagonize the Cannabinoid-1 (CBl) receptor.
  • compounds of the present invention are useful as psychotropic drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia.
  • the compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, marijuana, and nicotine, including smoking cessation.
  • the compounds are also useful for the treatment of obesity or eating disorders associated with excessive food intake and complications associated therewith.
  • the compounds are also useful for the treatment of constipation and chronic intestinal pseudo-obstruction.
  • the compounds are also useful for the treatment of cirrhosis of the liver.
  • the compounds are also useful for the treatment of asthma.
  • the present invention is also concerned with treatment of these conditions, and the use of compounds of the present invention for manufacture of a medicament useful in treating these conditions.
  • the present invention is also concerned with treatment of these conditions through a combination of compounds of formula I and other currently available pharmaceuticals.
  • the invention is also concerned with novel compounds of structural formula I.
  • the invention is also concerned with pharmaceutical formulations comprising one of the compounds as an active ingredient.
  • the invention is further concerned with processes for preparing the compounds of this invention.
  • Ci-ioalkyl (2) C3-iocycloalkyl, (3) cycloheteroalkyl,
  • heteroaryl wherein alky is optionally substituted with one, two, three or four substituents independently selected from R a , and each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are optionally substituted with one, two, three or four substituents independently selected from Rb;
  • R2 is selected from:
  • each alkyl is optionally substituted with one , two, three or four substituents independently selected from R a , and each cycloalkyl, and cycloheteroalkyl aryl and heteroaryl are optionally substituted with one, two, three or four substituents independently selected from Rb;
  • R3 is selected from:
  • R4 is selected from:
  • heteroaryl wherein alkyl, alkenyl, and alkynyl are optionally substituted with one, two, three or four substituents independently selected from R a , and aryl and heteroaryl are optionally substituted with one, two, three or four substituents independently selected from R D ;
  • R6 is selected from: (1) hydrogen,
  • alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents independently selected from R a ;
  • A is a 3- to 8-membered monocyclic saturated ring inco ⁇ orating the same carbon atom to which R4 is attached, and optionally containing one to two heteroatoms chosen from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one, two, three or four substituents independently selected from oxo and R D ; each R a is independently selected from: (1) -ORc,
  • each R D is independently selected from:
  • each R and R is independently selected from:
  • each Rg is independently selected from:
  • each R n is independently selected from:
  • each R 1 is ir idependently selected from:
  • Ci-ioalkyl (2) C2- 10 alkenyl,
  • each Ri may be unsubstituted or substituted with one, two, or three substituents selected from Rh; m is selected from 1 and 2; and n is selected from 1, 2, and 3; and pharmaceutically acceptable salts thereof.
  • Rl is selected from:
  • heteroaryl wherein each alkyl is optionally substituted with one to three substituents independently selected from Ra, and each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is optionally substituted with one to three substituents independently selected from Rb.
  • Rl is selected from:
  • Rl is selected from:
  • Rl is selected from aryl and pyridyl, wherein aryl and pyridyl are optionally substituted with one, two, three or four subsitutents independently selected from R D .
  • Rl is phenyl, wherein phenyl is optionally substituted with one, two, three or four substituents independently selected from Rb.
  • Rl is selected from:
  • Rl is selected from:
  • R2 is selected from:
  • each alkyl is optionally substituted with one, two or three substituents independently selected from R a
  • each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is optionally substituted with one, two or three substitutents independently selected from Rb.
  • R2 is selected from: (1) cyclobutyl
  • each alkyl is optionally substituted with one or two R a substituents and each phenyl or pyridyl is independently with one to three Rb substituents.
  • R is phenyl, wherein phenyl is optionally substituted with one, two, three or four substituents independently selected from Rb.
  • R2 is selected from:
  • R2 is selected from:
  • R3 is selected from:
  • R3 is selected from methyl and ethyl. In a subclass of this class, R3 is methyl.
  • R3 is hydrogen
  • R4 is selected from: (1) hydrogen,
  • heteroaryl wherein alkyl is optionally substituted with one, two, three or four substituents independently selected from R a , and aryl and heteroaryl are optionally substituted with one, two, three or four substituents independently selected from R b .
  • R4 is selected from:
  • alkyl groups may be optionally substituted with one, two, or three substituents independently selected from R a
  • phenyl, aryl and pyridyl are optionally substituted with one, two, three or four substituents independently selected from R D .
  • R4 is selected from: (1) hydrogen,
  • R6 is hydrogen.
  • the structural formula I may be represented as structural formula IA:
  • R6 is selected from:
  • alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents independently selected from R a .
  • R6 is selected from:
  • R6 is selected from: (1) methyl,
  • A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, mo ⁇ holinyl, tetrahydrofuranyl, and tetrahydropyranyl, each optionally substituted with one, two, three or four groups independently selected from oxo and Rb, with the proviso that when Rl and R are aryl and A is cyclobutyl, the cyclobutyl group is either unsubstituted, or is not substituted with an R a substituent selected from the group consisting of -OCH3, -
  • C(O)NRCRd, and -NRCC(O)NRCRd are not substituted with an R h substituent selected from the group consisting of: arylC ⁇ _4alkyl, heteroaryl, -NRCS(O) m Rd, - S(O) m NRCRd, -0(CReRf) n NRCRd, -C(O)RC j and -C(O)NRCRd.
  • A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, hexahydroazepinyl, mo ⁇ holinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrothienyl, each optionally substituted with one, two, or three groups independently selected from oxo and Rb.
  • A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, mo ⁇ holinyl, tetrahydrofuranyl, and tetrahydropyranyl, each optionally substituted with one or two groups independently selected from oxo and Rb.
  • A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, mo ⁇ holinyl, tetrahydrofuranyl, and tetrahydropyranyl, each optionally substituted with one or two groups independently selected from oxo and Rb, with the proviso that when A is cyclopropyl, the cyclopropyl group is not bis 2,2-dichlorocyclopropyl.
  • A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, mo ⁇ holinyl, tetrahydrofuranyl, and tetrahydropyranyl, each substituted with one group independently selected from Rb, with the proviso that when A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, Ra is not selected from the group consisting of -NRcS(O) m Rd, -NRcC(O)Rd, -NRcC(O)ORd, and -NRcC(O)NRCRd
  • R a is selected from:
  • R a is selected from:
  • R a is selected from:
  • Rb is selected from:
  • Rb is selected from:
  • R c and R are selected from:
  • R and Rd together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N-Rg, each Re and Rd may be unsubstituted or substituted with one, two or three substituents selected from Rb.
  • R c and Rd are selected from:
  • R c and Rd are independently selected from:
  • each R and Rd may be unsubstituted or substituted with one, two or three substituents selected from Rh.
  • Rg is selected from: (1) Ci-ioalkyl, and
  • Rb is selected from: (1) halogen, (2) ' Ci-ioalkyl, (3) C3_8cycloalkyl, (4) cycloheteroalkyl,
  • Rh is selected from: (1) halogen,
  • novel compounds of structural formula I which may be employed in the methods, uses and compositions of the present invention, include:
  • One subclass of compounds of the present invention includes compounds wherein Rl is 4-chlorophenyl, R2 is 4-chlorophenyl and R3 is methyl. Particular compounds of this subclass include:
  • the compounds of structural formula I are modulators of the CBl receptor.
  • the compounds of structural formula I are antagonists or inverse agonists of the CB 1 receptor.
  • An “agonist” is a compound (hormone, neurotransmitter or synthetic compound) which binds to a receptor-and produces a response, such as contraction, relaxation, secretion, change in enzyme activity, etc.
  • An “antagonist” is a compound which attenuates the effect of an agonist.
  • An “inverse agonist” is a compound which acts on a receptor but produces the opposite effect produced by the agonist of the particular receptor.
  • Alkyl as well as other groups having the prefix “alk”, such as alkoxy, alkanoyl, means carbon chains which may be linear or branched or combinations thereof.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.
  • alkenyl means carbon chains which contain at least one carbon- carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1- propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.
  • alkynyl means carbon chains which contain at least one carbon- carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-l-pentynyl, 2-heptynyl and the like.
  • Cycloalkyl means mono- or bicyclic or bridged saturated carbocyclic rings, each of which having from 3 to 10 carbon atoms. The term also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like.
  • Aryl means mono- or bicyclic aromatic rings containing only carbon atoms.
  • the term also includes aryl group fused to a monocyclic cycloalkyl or monocyclic cycloheteroalkyl group in which the point of attachment is on the aromatic portion.
  • aryl include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1,4- benzodioxanyl, and the like.
  • Heteroaryl means a mono- or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, with each ring containing 5 to 6 atoms.
  • heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, and the like.
  • the heteroaryl ring may be substituted on one or more carbon atoms.
  • “Cycloheteroalkyl” means mono- or bicyclic or bridged saturated rings containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen.
  • the term also includes monocyclic heterocycle fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion.
  • cycloheteroalkyl examples include pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 2,3- dihydrofuro(2,3-b)pyridyl, benzoxazinyl, tetrahydrohydroquinolinyl, mo ⁇ holinyl, tetrahydroisoquinolinyl, dihydroindolyl, and the like.
  • the term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones attached through the nitrogen or N-substituted-(lH, 3H)-pyrimidine-2,4-diones (N-substituted uracils).
  • the cycloheteroalkyl ring may be substituted on the ring carbons and/or the ring nitrogens.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • variable e.g., Rl, Rd, etc.
  • its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • substituted shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.
  • Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, enantiomeric mixtures, diastereomeric mixtures and individual diastereomers.
  • the present invention is meant to comprehend all such isomeric forms of the compounds of Formula I.
  • Tautomers are defined as compounds that undergo rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I. By way of illustration, tautomers included in this definition include, but are not limited to:
  • Compounds of the Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example MeOH or ethyl acetate or a mixture thereof.
  • a suitable solvent for example MeOH or ethyl acetate or a mixture thereof.
  • the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active amine as a resolving agent or on a chiral HPLC column.
  • any enantiomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
  • crystalline forms for compounds of the present invention may exist as polymo ⁇ hs and as such are intended to be included in the present invention.
  • some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
  • Racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. These include chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethyl-mo ⁇ holine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, mo ⁇ holine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine
  • pharmaceutically acceptable salt further includes all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycollyl
  • references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
  • Compounds of this invention are modulators of the CBl receptor and as such are useful as psychotropic drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia.
  • the compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, marijuana, and nicotine.
  • the compounds are also useful for the treatment of obesity or eating disorders associated with excessive food intake and complications associated therewith.
  • the compounds are also useful for the treatment of constipation and chronic intestinal pseudo-obstruction.
  • the compounds are also useful for the treatment of cirrhosis of the liver.
  • the compounds are also useful for the treatment of asthma.
  • administering should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
  • the administration of the compound of structural formula I in order to practice the present methods of therapy is carried out by administering an effective amount of the compound of structural formula I to the patient in need of such treatment or prophylaxis.
  • the need for a prophylactic administration according to the methods of the present invention is determined via the use of well known risk factors.
  • the effective amount of an individual compound is determined, in the final analysis, by the physician in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions from which the patient suffers, the chosen route of administration other drugs and treatments which the patient may concomitantly require, and other factors in the physician's judgment.
  • the compounds of this invention are also useful for the treatment or prevention of conditions associated with, caused by, or resulting from obesity.
  • the compounds are useful for reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy.
  • Formula I will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
  • a suitable dosage range is from about 0.001 mg to about 100 mg (preferably from 0.01 mg to about 50 mg, more preferably 0.1 mg to 10 mg) of a compound of Formula I per kg of body weight per day.
  • a suitable dosage range is, e.g. from about 0.01 mg to about 1000 mg of a compound of Formula I per day, preferably from about 0.1 mg to about 10 mg per day.
  • the compositions are preferably provided in the form of tablets containing from 0.01 to 1,000 mg, preferably 0.01, 0.05, 0.1, 0.5, 1, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 100, 250, 500, 750 or 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • compositions which comprises a compound of Formula I and a pharmaceutically acceptable carrier.
  • composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of Formula I, additional active ingredient(s), and pharmaceutically acceptable excipients.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
  • the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulizers.
  • the compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device.
  • the preferred delivery systems for inhalation are metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of Formula I in suitable propellants, such as fluorocarbons or hydrocarbons and dry powder inhalation (DPI) aerosol, which may be formulated as a dry powder of a compound of Formula I with or without additional excipients.
  • MDI metered dose inhalation
  • DPI dry powder inhalation
  • Suitable topical formulations of a compound of formula I include transdermal devices, aerosols, creams, solutions, ointments, gels, lotions, dusting powders, and the like.
  • the topical pharmaceutical compositions containing the compounds of the present invention ordinarily include about 0.005% to 5% by weight of the active compound in admixture with a pharmaceutically acceptable vehicle.
  • Transdermal skin patches useful for administering the compounds of the present invention include those well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course be continuous rather than intermittent throughout the dosage regimen.
  • the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
  • the compounds of Formula I may also be administered by controlled release means and/or delivery devices such as those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules (including timed release and sustained release formulations), pills, cachets, powders, granules or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion, including elixirs, tinctures, solutions, suspensions, syrups and emulsions.
  • Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • each tablet contains from 0.01 to 1,000 mg, particularly 0.01, 0.05, 0.1, 0.5, 1, 2.5, 3, 5, 6, 10, 15, 25, 50, 75, 100, 125, 150, 175, 180, 200, 225, 500, 750 and 1,000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated
  • each cachet or capsule contains from about 0.01 to 1,000 mg, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 3, 5, 6, 10, 15/25, 50, 75, 100, 125, 150, 175, 180, 200, 225, 500, 750 and 1,000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • Additional suitable means of administration of the compounds of the present invention include injection, intravenous bolus or infusion, intraperitoneal, subcutaneous, intramuscular and topical, with or without occlusion.
  • Exemplifying the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. Also exemplifying the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. An illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
  • the dose may be administered in a single daily dose or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, based on the properties of the individual compound selected for administration, the dose may be administered less frequently, e.g., weekly, twice weekly, monthly, etc. The unit dosage will, of course, be correspondingly larger for the less frequent administration.
  • the dosage administration When administered via intranasal routes, transdermal routes, by rectal or vaginal suppositories, or through a continual intravenous solution, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • Compounds of Formula I may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula I are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I.
  • a pharmaceutical composition containing such other drugs in addition to the compound of Formula I is preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula I.
  • Examples of other active ingredients that may be combined with a compound of Formula I include, but are not limited to: antipsychotic agents, cognition enhancing agents, anti-migraine agents, anti -asthmatic agents, antiinflammatory agents, anxiolytics, anti-Parkinson's agents, anti-epileptics, anorectic agents, serotonin reuptake inhibitors, and other anti-obesity agents, which may be administered separately or in the same pharmaceutical compositions.
  • the present invention also provides a method for the treatment or prevention of a CBl receptor modulator mediated disease, which method comprises administration to a patient in need of such treatment or at risk of developing a CBl receptor modulator mediated disease of an amount of a CBl receptor modulator and an amount of one or more active ingredients, such that together they give effective relief.
  • a pharmaceutical composition comprising a CB 1 receptor modulator and one or more active ingredients, together with at least one pharmaceutically acceptable carrier or excipient.
  • a CBl receptor modulator and one or more active ingredients for the manufacture of a medicament for the treatment or prevention of a CBl receptor modulator mediated disease.
  • a product comprising a CBl receptor modulator and one or more active ingredients as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of CBl receptor modulator mediated disease.
  • Such a combined preparation may be, for example, in the form of a twin pack. It will be appreciated that for the treatment or prevention of eating disorders, including obesity, bulimia nervosa and compulsive eating disorders, a compound of the present invention may be used in conjunction with other anorectic agents.
  • the present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an anorectic agent, such that together they give effective relief.
  • Suitable anoretic agents of use in combination with a compound of the present invention include, but are not limited to, aminorex, amphechloral, amphetamine, benzphetamine, chlo ⁇ hentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, no ⁇ seudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine,
  • a particularly suitable class of anorectic agent are the halogenated amphetamine derivatives, including chlo ⁇ hentermine, cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine; and pharmaceutically acceptable salts thereof
  • Particularly preferred halogenated amphetamine derivatives of use in combination with a compound of the present invention include: fenfluramine and dexfenfluramine, and pharmaceutically acceptable salts thereof.
  • the compounds of the present invention may also be used in combination with a selective serotonin reuptake inhibitor (SSRI).
  • SSRI selective serotonin reuptake inhibitor
  • the present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an SSRI, such that together they give effective relief.
  • Suitable selective serotonin reuptake inhibitors of use in combination with a compound of the present invention include: fluoxetine, fluvoxamine, paroxetine sertraline, and imipramine, and pharmaceutically acceptable salts thereof.
  • the compounds of the present invention may also be used in combination with an opioid antagonist.
  • the present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an opioid antagonist, such that together they give effective relief.
  • Suitable opioid antagonists of use in combination with a compound of the present invention include: naltrexone, 3-methoxynaltrexone, naloxone and nalmefene, and pharmaceutically acceptable salts thereof.
  • the compounds of the present invention may also be used in combination with another anti-obesity agent.
  • the present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of another anti-obesity agent, such that together they give effective relief.
  • Suitable anti-obesity agents of use in combination with a compound of the present invention include, but are not limited to: 1) growth hormone secretagogues, such as those disclosed and specifically described in U.S.
  • Patent 5,536,716 2) growth hormone secretagogue receptor agonists/antagonists, such as NN703, hexarelin, MK-0677, SM-130686, CP-424,391, L-692,429 and L-163,255, and such as those disclosed in U.S. Patent No. 6,358,951, U.S. Patent Application Nos. 2002/049196 and 2002/022637, and PCT Application Nos.
  • WO 01/56592 and WO 02/32888 3) melanocortin agonists, such as Melanotan II or those described in WO 99/64002 and WO 00/74679; 4) Mc4r (melanocortin 4 receptor) agonists, such as CHIR86036 (Chiron), ME-10142, and ME-10145 (Melacure), and those disclosed in PCT Application Nos.
  • melanocortin agonists such as Melanotan II or those described in WO 99/64002 and WO 00/74679
  • Mc4r (melanocortin 4 receptor) agonists such as CHIR86036 (Chiron), ME-10142, and ME-10145 (Melacure), and those disclosed in PCT Application Nos.
  • ⁇ -3 agonists such as AD9677/TAK677 (Dainippon/Takeda), CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, Trecadrine, Zeneca D7114, SR 59119A, and such as those disclosed in U.S. Patent Application Nos.
  • JP 13226269 11) melanin-concentrating hormone 2 receptor (MCH2R) agonist/antagonists; 12) galanin antagonists; 13) CCK agonists; 14) CCK-A (cholecystokinin -A) agonists, such as AR-R 15849, GI 181771, JMV-180, A-71378, A-71623 and SR146131, and those discribed in U.S. Patent No.
  • GLP-1 agonists such as GW-569180A, GW- 594884A, GW-587081X, GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170, SR-120562A, SR- 120819A and JCF-104, and those disclosed in U.S. Patent Nos.
  • WO 97/19682 WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 98/27063, WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/14376, WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO 02/22592, WO 0248152, and WO 02/49648; 18) NPY 1 antagonists, such as BIBP3226, J-l 15814, BIBO 3304, LY-357897, CP-671906, GI- 264879A, and those disclosed in U.S.
  • NPY 1 antagonists such
  • ⁇ -HSD-1 ⁇ -hydroxy steroid dehydrogenase-1 inhibitors
  • PDE phosphodiesterase
  • NE neuropeptide-like steroid dehydrogenase-1 inhibitors
  • GW 320659 despiramine, talsupram, and nomifensine
  • non-selective serotonin/norepinephrine transport inhibitors such as sibutramine or fenfluramine
  • ghrelin antagonists ⁇ -hydroxy steroid dehydrogenase-1 inhibitors
  • leptin including recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen); 28) leptin derivatives, such as those disclosed in U.S. Patent Nos. 5,552,524, 5,552,523, 5,552,522, 5,521,283, and PCT International Publication Nos.
  • WO 94/09134 WO 98/22128, and WO 99/43813; 32) monoamine reuptake inhibitors, such as those disclosed in PCT Application Nos. WO 01/27068, and WO 01/62341; 33) UCP-1 (uncoupling protein-1), 2, or 3 activators, such as phytanic acid, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- napthalenyl)-l-propenyl]benzoic acid (TTNPB), retinoic acid, and those disclosed in PCT Patent Application No.
  • WO 99/00123 thyroid hormone ⁇ agonists, such as KB-2611 (KaroBioBMS), and those disclosed in PCT Application No. WO 02/15845, and Japanese Patent Application No. JP 2000256190; 35) FAS (fatty acid synthase) inhibitors, such as Cerulenin and C75; 36) DGATl (diacylglycerol acyltransferase 1) inhibitors; 37) DGAT2 (diacylglycerol acyltransferase 2) inhibitors; 38) ACC2 (acetyl-CoA carboxylase-2) inhibitors; 39) glucocorticoid antagonists; 40) acyl- estrogens, such as oleoyl-estrone, disclosed in del Mar-Grasa, M.
  • acyl- estrogens such as oleoyl-estrone, disclosed in del Mar-Grasa, M.
  • lipase inhibitors such as orlistat (Xenical®), Triton WR1339, RHC80267, lipstatin, tetrahydrolipstatin, teasaponin, diethylumbelliferyl phosphate, and those disclosed in PCT Application No. WO 01/77094; 42) fatty acid transporter inhibitors; 43) dicarboxylate transporter inhibitors; 44) glucose transporter inhibitors; 45) phosphate transporter inhibitors; 46) serotonin reuptake inhibitors, such as those disclosed in U.S. Patent Application No. 6,365,633, and PCT Patent Application Nos. WO 01/27060, and WO 01/162341 ; 47) Metformin (Glucophage®); and or 48) Topiramate (Topimax®).
  • orlistat Xenical®
  • Triton WR1339, RHC80267 lipstatin
  • tetrahydrolipstatin teasaponin
  • NPY5 antagonists of use in combination with a compound of the present invention are selected from the group consisting of:
  • “Obesity” is a condition in which there is an excess of body fat.
  • the operational definition of obesity is based on the Body Mass Index (BMI), which is calculated as body weight per height in meters squared (kg/m2).
  • BMI Body Mass Index
  • “Obesity” refers to a condition whereby an otherwise healthy subject has a Body Mass Index (BMI) greater than or equal to 30 kg/m2, or a condition whereby a subject with at least one co- morbidity has a BMI greater than or equal to 27 kg/m2.
  • An “obese subject” is an otherwise healthy subject with a Body Mass Index (BMI) greater than or equal to 30 kg/m2 or a subject with at least one co-morbidity with a BMI greater than or equal to 27 kg/m2.
  • a "subject at risk for obesity” is an otherwise healthy subject with a BMI of 25 kg/m2 to less than 30 kg/m2 or a subject with at least one co-morbidity with a BMI of 25 kg/m2 to less than 27 kg/m2.
  • BMI Body Mass Index
  • “obesity” refers to a condition whereby a subject with at least one obesity-induced or obesity-related co- morbidity that requires weight reduction or that would be improved by weight reduction, has a BMI greater than or equal to 25 kg/m2.
  • an “obese subject” refers to a subject with at least one obesity-induced or obesity-related co-morbidity that requires weight reduction or that would be improved by weight reduction, with a BMI greater than or equal to 25 kg/m2.
  • a "subject at risk of obesity” is a subject with a BMI of greater than 23 kg/m2 to less than 25 kg/m2.
  • Obesity is meant to encompass all of the above definitions of obesity.
  • Obesity-induced or obesity-related co-morbidities include, but are not limited to, diabetes, non-insulin dependent diabetes mellitus - type 2, impaired glucose tolerance, impaired fasting glucose, insulin resistance syndrome, dyslipidemia, hypertension, hyperuricacidemia, gout, coronary artery disease, myocardial infarction, angina pectoris, sleep apnea syndrome, Pickwickian syndrome, fatty liver; cerebral infarction, cerebral thrombosis, transient ischemic attack, orthopedic disorders, arthritis deformans, lumbodynia, emmeniopathy, and infertility.
  • co-morbidities include: hypertension, hyperlipidemia, dyslipidemia, glucose intolerance, cardiovascular disease, sleep apnea, diabetes mellitus, and other obesity-related conditions.
  • Treatment refers to the administration of the compounds of the present invention to reduce or maintain the body weight of an obese subject.
  • One outcome of treatment may be reducing the body weight of an obese subject relative to that subject's body weight immediately before the administration of the compounds of the present invention.
  • Another outcome of treatment may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy.
  • Another outcome of treatment may be decreasing the occurrence of and/or the severity of obesity-related diseases.
  • the treatment may suitably result in a reduction in food or calorie intake by the subject, including a reduction in total food intake, or a reduction of intake of specific components of the diet such as carbohydrates or fats; and/or the inhibition of nutrient abso ⁇ tion; and/or the inhibition of the reduction of metabolic rate; and in weight reduction in patients in need thereof.
  • the treatment may also result in an alteration .of metabolic rate, such as an increase in metabolic rate, rather than or in addition to an inhibition of the reduction of metabolic rate; and/or in minimization of the metabolic resistance that normally results from weight loss.
  • "Prevention" (of obesity and obesity-related disorders) refers to the administration of the compounds of the present invention to reduce or maintain the body weight of a subject at risk of obesity.
  • One outcome of prevention may be reducing the body weight of a subject at risk of obesity relative to that subject's body weight immediately before the administration of the compounds of the present invention. Another outcome of prevention may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy. Another outcome of prevention may be preventing obesity from occurring if the treatment is administered prior to the onset of obesity in a subject at risk of obesity. Another outcome of prevention may be decreasing the occurrence and/or severity of . obesity- related disorders if the treatment is administered prior to the onset of obesity in a subject at risk of obesity.
  • Such treatment may prevent the occurrence, progression or severity of obesity-related disorders, such as, but not limited to, arteriosclerosis, Type II diabetes, polycystic ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
  • the obesity-related disorders herein are associated with, caused by, or result from obesity.
  • obesity-related disorders include overeating and bulimia, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovarian disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, GH-deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g, children with acute lymphoblastic leukemia.
  • obesity-related disorders are metabolic syndrome, also known as syndrome X, insulin resistance syndrome, sexual and reproductive dysfunction, such as infertility, hypogonadism in males and hirsutism in females, gastrointestinal motility disorders, such as obesity-related gastro-esophageal reflux, respiratory disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, and kidney cancer.
  • the compounds of the present invention are also useful for reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy.
  • diabetes includes both insulin- dependent diabetes mellitus (i.e., IDDM, also known as type I diabetes) and non- insulin-dependent diabetes mellitus (i.e., NEDDM, also known as Type II diabetes.
  • IDDM insulin- dependent diabetes mellitus
  • NEDDM non- insulin-dependent diabetes mellitus
  • Type I diabetes or insulin-dependent diabetes
  • Type II diabetes is the result of an absolute deficiency of insulin, the hormone which regulates glucose utilization.
  • Type II diabetes, or insulin-independent diabetes i.e., non-insulin-dependent diabetes mellitus
  • Most of the Type II diabetics are also obese.
  • the compounds of the present invention are useful for treating both Type I and Type II diabetes.
  • the compounds are especially effective for treating Type IT diabetes.
  • the compounds of the present invention are also useful for treating and/or preventing gestational diabetes mellitus.
  • a compound of the present invention may be used in conjunction with other anti- migraine agents, such as ergotamines or 5-HT ⁇ agonists, especially sumatriptan, naratriptan, zolmatriptan or rizatriptan.
  • a compound of the present invention may be used in conjunction with other anti- depressant or anti-anxiety agents.
  • Suitable classes of anti-depressant agents include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, ⁇ -adrenoreceptor antagonists, neurokinin-1 receptor antagonists and atypical anti-depressants.
  • Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics.
  • Suitable examples of tertiary amine tricyclics include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine, and pharmaceutically acceptable salts thereof.
  • Suitable examples of secondary amine tricyclics include: amoxapine, desipramine, maprotiline, nortriptyline and protriptyline, and pharmaceutically acceptable salts thereof.
  • Suitable selective serotonin reuptake inhibitors include: fluoxetine, fluvoxamine, paroxetine, imipramine and sertraline, and pharmaceutically acceptable salts thereof.
  • Suitable monoamine oxidase inhibitors include: isocarboxazid, phenelzine, tranylcypromine and selegiline, and pharmaceutically acceptable salts thereof.
  • Suitable reversible inhibitors of monoamine oxidase include: moclobemide, and pharmaceutically acceptable salts thereof.
  • Suitable serotonin and noradrenaline reuptake inhibitors of use in the present invention include: venlafaxine, and pharmaceutically acceptable salts thereof.
  • Suitable CRF antagonists include those compounds described in International Patent Specification Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677.
  • Suitable neurokinin-1 receptor antagonists may be peptidal or non- peptidal in nature, however, the use of a non-peptidal neurokinin-1 receptor antagonist is preferred.
  • the neurokinin-1 receptor antagonist is a CNS-penetrant neurokinin-1 receptor antagonist.
  • an orally active neurokinin-1 receptor antagonist is preferred.
  • the neurokinin-1 receptor antagonist is a long acting neurokinin-1 receptor antagonist.
  • An especially preferred class of neurokinin-1 receptor antagonists of use in the present invention are those compounds which are orally active and long acting.
  • Neurokinin-1 receptor antagonists of use in the present invention are fully described, for example, in U.S. Patent Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699; European Patent Publication Nos.
  • Neurokinin-1 receptor antagonists of use in the present invention include:
  • Suitable atypical anti -depressants include: bupropion, lithium, nefazodone, trazodone and viloxazine, and pharmaceutically acceptable salts thereof.
  • Suitable classes of anti-anxiety agents include benzodiazepines and 5-HTi A agonists or antagonists, especially 5-HTi A partial agonists, and corticotropin releasing factor (CRF) antagonists.
  • Suitable benzodiazepines include: alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam, and pharmaceutically acceptable salts thereof.
  • Suitable 5-HT A receptor agonists or antagonists include, in particular, the 5-HTi A receptor partial agonists buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.
  • Suitable corticotropin releasing factor (CRF) antagonists include those previously discussed herein.
  • substance abuse disorders includes substance dependence or abuse with or without physiological dependence.
  • the substances associated with these disorders are: alcohol, amphetamines (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, marijuana, nicotine, opioids, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics or benzodiazepines, and other (or unknown) substances and combinations of all of the above.
  • the term "substance abuse disorders” includes drug withdrawal disorders such as alcohol withdrawal with or without perceptual disturbances; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without perceptual disturbances; sedative, hypnotic or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances. It will be appreciated that reference to treatment of nicotine withdrawal includes the treatment of symptoms associated with smoking cessation.
  • substance abuse disorders include substance-induced anxiety disorder with onset during withdrawal; substance-induced mood disorder with onset during withdrawal; and substance-induced sleep disorder with onset during withdrawal.
  • a combination of a conventional antipsychotic drug with a CBl receptor modulator may provide an enhanced effect in the treatment of mania. Such a combination would be expected to provide for a rapid onset of action to treat a manic episode thereby enabling prescription on an "as needed basis". Furthermore, such a combination may enable a lower dose of the antispychotic agent to be used without compromising the efficacy of the antipsychotic agent, thereby minimizing the risk of adverse side-effects.
  • a yet further advantage of such a combination is that, due to the action of the CBl receptor modulator, adverse side-effects caused by the antipsychotic agent such as acute dystonias, dyskinesias, akathesia and tremor may be reduced or prevented.
  • the present invention also provides a method for the treatment or prevention of mania, which method comprises administration to a patient in need of such treatment or at risk of developing mania of an amount of a CB 1 receptor modulator and an amount of an antipsychotic agent, such that together they give effective relief.
  • a pharmaceutical composition comprising a CBl receptor modulator and an antipsychotic agent, together with at least one pharmaceutically acceptable carrier or excipient.
  • the CBl receptor modulator and the antipsychotic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of mania.
  • Such combined preparations may be, for example, in the form of a twin pack.
  • a product comprising a CBl receptor modulator and an antipsychotic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of mania.
  • the CBl receptor modulator and the antipsychotic agent may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously.
  • the term “combination” also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. Therefore, by way of example, the antipsychotic agent may be administered as a tablet and then, within a reasonable period of time, the CBl receptor modulator may be administered either as an oral dosage form such as a tablet or a fast-dissolving oral dosage form.
  • a fast-dissolving oral formulation is meant, an oral delivery form which when placed on the tongue of a patient, dissolves within about 10 seconds.
  • CB 1 receptor modulators in combination with an antipsychotic agent in the treatment or prevention of hypomania.
  • a combination of a conventional antipsychotic drug with a CBl receptor modulator may provide an enhanced effect in the treatment of schizophrenic disorders. Such a combination would be expected to provide for a rapid onset of action to treat schizophrenic symptoms thereby enabling prescription on an "as needed basis". Furthermore, such a combination may enable a lower dose of the CNS agent to be used without compromising the efficacy of the antipsychotic agent, thereby minimizing the risk of adverse side-effects.
  • a yet further advantage of such a combination is that, due to the action of the CBl receptor modulator, adverse side-effects caused by the antipsychotic agent such as acute dystonias dyskinesias, akathesia and tremor may be reduced or prevented.
  • the term "schizophrenic disorders” includes paranoid, disorganized, catatonic, undifferentiated and residual schizophrenia; schizophreniform disorder; schizoaffective disorder; delusional disorder; brief psychotic disorder; shared psychotic disorder; substance-induced psychotic disorder; and psychotic disorder not otherwise specified.
  • schizophrenic disorders include self-injurious behavior (e.g. Lesch-Nyhan syndrome) and suicidal gestures.
  • Suitable antipsychotic agents of use in combination with a CBl receptor modulator include the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of antipsychotic agent.
  • Suitable examples of phenothiazines include chlo ⁇ romazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, pe ⁇ henazine and trifluoperazine.
  • Suitable examples of thioxanthenes include chlo ⁇ rothixene and thiothixene.
  • Suitable examples of dibenzazepines include clozapine and olanzapine.
  • An example of a butyrophenone is haloperidol.
  • An example of a diphenylbutylpiperidine is pimozide.
  • An example of an indolone is molindolone.
  • Other antipsychotic agents include loxapine, sulpiride and risperidone.
  • the antipsychotic agents when used in combination with a CBl receptor modulator may be in the form of a pharmaceutically acceptable salt, for example, chlo ⁇ romazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flu ⁇ henazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride.
  • Pe ⁇ henazine, chlo ⁇ rothixene, clozapine, olanzapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form.
  • D3 dopamine receptor antagonist is the compound PNU-99194A.
  • D4 dopamine receptor antagonist is PNU-101387.
  • a muscarinic ml receptor agonist is xanomeline.
  • Another class of antipsychotic agent of use in combination with a CBl receptor modulator is the 5-HT2A receptor antagonists, examples of which include MDL100907 and fananserin. Also of use in combination with a CBl receptor modulator are the serotonin dopamine antagonists (SDAs) which are believed to combine 5-HT2A and dopamine receptor antagonist activity, examples of which include olanzapine and ziperasidone.
  • SDAs serotonin dopamine antagonists
  • NK-1 receptor antagonists may be favorably employed with the CBl receptor modulators of the present invention.
  • Preferred NK-1 receptor antagonists for use in the present invention are selected from the classes of compounds described in European Patent Specification No. 0 577 394, and
  • NK-1 receptor antagonists of use in the present invention include: (3S,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6- phenyl-l-oxa-7-aza-spiro[4.5]decane;
  • a combination of a conventional anti- asthmatic drug with a CB 1 receptor modulator may provide an enhanced effect in the treatment of asthma.
  • a CB 1 receptor modulator and an anti-asthmatic agent for the manufacture of a medicament for the treatment or prevention of asthma.
  • the present invention also provides a method for the treatment or prevention of asthma, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an anti-asthmatic agent, such that together they give effective relief.
  • Suitable anti-asthmatic agents of use in combination with a compound of the present invention include, but are not limited to: (a) VLA-4 antagonists such as natalizumab and the compounds described in US 5,510,332, WO97/03094, WO97/02289, WO96/40781, WO96/22966, WO96/20216, WO96/01644,
  • WO96/06108 WO95/15973 and WO96/31206
  • steroids and corticosteroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone
  • antihistamines HI -histamine antagonists
  • a combination of a conventional anti- constipation drug with a CBl receptor modulator may provide an enhanced effect in the treatment of constipation.
  • a CBl receptor modulator and an anti-constipation agent for the manufacture of a medicament for the treatment or prevention of constipation.
  • the present invention also provides a method for the treatment or prevention of constipation, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an anti-constipation agent, such that together they give effective relief.
  • a combination of a conventional anti- constipation drug with a CB 1 receptor modulator may provide an enhanced effect in the treatment of chronic intestinal pseudo-obstruction.
  • a CBl receptor modulator and an anti-constipation agent for the manufacture of a medicament for the treatment or prevention of chronic intestinal pseudo-obstruction .
  • the present invention also provides a method for the treatment or prevention of chronic intestinal pseudo-obstruction, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an anti-constipation agent, such that together they give effective relief.
  • Suitable anti-constipation agents of use in combination with a compound of the present invention include, but are not limited to, osmotic agents, laxatives and detergent laxatives (or wetting agents), bulking agents, and stimulants; and pharmaceutically acceptable salts thereof.
  • a particularly suitable class of osmotic agents include, but are not limited to sorbitol, lactulose, polyethylene glycol, magnesium, phosphate,and sulfate; and pharmaceutically acceptable salts thereof.
  • a particularly suitable class of laxatives and detergent laxatives include, but are not limited to, magnesium, and docusate sodium; and pharmaceutically acceptable salts thereof.
  • a particularly suitable class of bulking agents include, but are not limited to, psyllium, methylcellulose, and calcium polycarboph.il; and pharmaceutically acceptable salts thereof.
  • a particularly suitable class of stimulants include, but are not limited to, anthroquinones, and phenolphthalein; and pharmaceutically acceptable salts thereof.
  • a combination of a conventional anti- cirrhosis drug with a CB 1 receptor modulator may provide an enhanced effect in the treatment'of cirrhosis of the liver.
  • a CBl receptor modulator and an anti-cirrhosis agent for the manufacture of a medicament for the treatment or prevention of cirrhosis of the liver.
  • the present invention also provides a method for the treatment or prevention of cirrhosis of the liver, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an anti-cirrhosis agent, such that together they give effective relief.
  • Suitable anti-cirrhosis agents of use in combination with a compound of the present invention include, but are not limited to, corticosteroids, penicillamine, colchicine, interferon- ⁇ , 2-oxoglutarate analogs, prostaglandin analogs, and other anti- inflammatory drugs and antimetabolites such as azathioprine, methotrexate, leflunamide, indomethacin, naproxen, and 6-mercaptopurine; and pharmaceutically acceptable salts thereof.
  • the method of treatment of this invention comprises a method of modulating the CB 1 receptor and treating CB 1 receptor mediated diseases by administering to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of this invention that selectively antagonizes the CBl receptor in preference to the other CB or G-protein coupled receptors.
  • terapéuticaally effective amount means the amount the compound of structural formula I that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disorder being treated.
  • the novel mehtods of treatment of this invention are for disorders known to those skilled in the art.
  • the term "mammal” includes humans.
  • the weight ratio of the compound of the Formula I to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • the weight ratio of the compound of the Formula I to the ⁇ -3 agonist will generally range from about 1000: 1 to about 1 : 1000, preferably about 200: 1 to about 1 :200.
  • Combinations of a compound of the Formula I and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be' used.
  • API-ES atmospheric pressured ionization-electrospray (mass spectrum term)
  • CDCI3 chloroform, deuterated
  • HOBt 1 -hydroxybenzotri azole
  • LC/MS analyses were preformed using a Micromass ZMD mass spectrometer coupled to an Agilent 1100 Series HPLC utilizing a YMC ODS-A 4.6 x
  • Step B 3-(4-Chlorophenyl)-2-phenylpropanoic acid
  • acetonitrile 100 mL
  • water 100 mL
  • lithium hydroxide monohydrate 8.8 g, 0.21 mol
  • the volatile materials were removed by concentrating on a rotary evaporator and the residue was partitioned between water (300 mL) and hexane/ether (1:1, 200 mL).
  • Step D 4-(4-Chlorophenyl)-3-phenyl-2-butanone To a solution of N-methoxy-N-methyl-3-(4-chlorophenyl)-2-phenylpropanamide (Step C, 16 g, 53 mmol, dried by azeotroping with toluene) in anhydrous tetrahydrofuran (200 mL) at 0°C was added methylmagnesium bromide (3 M in ether, 35 mL, 0.11 mol).
  • Step D To a solution of 4-(4-chlorophenyl)-3-phenyl-2-butanone (Step D, 13 g, 50 mmol) in methanol (100 mL) at 0°C was added sodium borohydride (3.8 g, 100 mmol). After stirring at 0°C for 30 min, the reaction was quenched by adding 2 M hydrochloric acid (50 mL). The volatile materials were removed by concentrating on a rotary evaporator and the residue partitioned between water (100 mL) and ethyl acetate (200 mL).
  • Step I N-r3-(4-Chlorophenyl)-2-phenyl-l-methylpropyl1-amine hydrochloride (Diastereomer ⁇ ).
  • Step B N-r3-(4-chlorophenyl)-2(S)-phenyl-l(S)-methylpropyll-amine, hydrochloride
  • the product of Step A (4-(4-chlorophenyl)-3(S)-phenyl-2(R)-butanol, 1.8 g, 7.0 mmol) was converted to the title compound following the steps described in Reference Example 2, Steps F through I, except hydrogen chloride in dioxane (4 M) was used in place of hydrogen chloride in ethyl acetate.
  • lH ⁇ MR 500 MHz, CD3OD
  • ⁇ 7.35-6.98 (m, 9H), 3.62 (m, IH), 3.20 (dd, IH), 3.05 (m, IH), 2.98 (dd,
  • Step B N-[3-(4-chlorophenyl)-2-(3-pyridyl)-l-methylpropyll-amine, hydrochloride (mixture of diastereomers ⁇ / ⁇ 10:1)
  • the product of Step 1 (4-(4-chlorophenyl)-3-pyridyl-2-butanone) was converted to the title compound following the procedure described in Reference Example 2, Steps E through I.
  • Step B N-Methoxy-N-methyl-3-(4-chlorophenyl)-2-(3- fluororophenvPpropanamide
  • N-methoxy-N-methylamine hydrochloride 2.0 g, 21 mmol
  • dimethylaluminum chloride 1 M in hexane, 21 mL, 21 mmol
  • a solution of methyl 3- (4-chlorophenyl)-2-(3-flurophenyl)propionate (Step 1, 2.0 g, 10 mmol) in methylene chloride (10 mL) was added, and the resulting mixture was stirred overnight.
  • Step C 4-(4-Chloro ⁇ henyl)-3-(3-fluoro ⁇ henyl)-2-butanoI
  • the product of Step 2 (N-methoxy-N-methyl-3-(4-chlorophenyl)-2- phenylpropionamide) (0.74 g, 2.3 mmol) was converted to the title compound as a 5:1 mixture of diastereomers following the procedure described in Reference Example 2, Steps D through E. lH ⁇ MR (400 MHz, CD3OD): ⁇ 7.22-6.78 (m, 8H), 3.98 (m,
  • Step E 2-Amino-4-(4-Chlorophenyl)-3-(3-fluorophenvDbutane hydrochloride salt (mixture of diastereomers ⁇ / ⁇ 5:1)
  • the product of Step D (2-azido-4-(4-chlorophenyl)-3-(3-fluorophenyl)butane) (0.49 g, 1.6 mmol) was converted to the title compound following the steps described in Reference Example 2, Steps H - 1. lH NMR (400 MHz, CD3OD): ⁇ 7.32-6.90 (m,
  • Trimethylaluminum was used in place of dimethylaluminum chloride at Step B of Reference Example 5.
  • LC-MS m/e 261 (M + H) + .
  • Step B l-tert-Butoxycarbonyl-3-ethylazetidine-3-carboxylic Acid
  • Step A . l-(3-bromophenyl)acetone
  • N-methoxy-N-methylacetamide 10 g, 0.10 mol
  • 3-bromobenzylmagnesium bromide 0.25 M, 200 mL, 50 mmol
  • the reaction mixture was partitioned between hexane and saturated aqueous ammonium chloride.
  • the organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness to give the title compound, which was used without further purification.
  • H NMR 500 MHz, CD3OD: ⁇ 7.5-7.1 (m, 4H), 3.78 (s, 2H), 2.19 (s, 3H).
  • Step B 3-(3-Bromophenyl)-2-butanone.
  • Step C 3-(3-Bromophenyl)-4-(4-chlorophenyl)-3-methyl-2-butanone.
  • Step D 3-(3-Bromophenyl)-4-(4-chlorophenyl)-3-methyl-2-butanol.
  • Step F 2-(N-tert-Butoxycarbonyl)amino-3-(3-bromophenyl)-4-(4- chlorophen yl)-3-meth ylbutane
  • 2-azido-3-(3-bromophenyl)-4-(4-chlorophenyl)-3-methylbutane (Diastereomer ⁇ , 0.26 g, 0.68 mmol) in ethyl acetate (5 mL) was added di(tert- butyl)dicarbonate (0.18 g, 0.82 mmol) and platinum dioxide (0.025 g).
  • the mixture was degassed and charged with hydrogen with a balloon. After stirring for 1 day, the reaction mixture was filtered through CELITE, diatomaceous earth, and the filtrate was concentrated to give diastereomer ⁇ of the title compound.
  • Diastereomer ⁇ of 2-azido-3-(3-bromophenyl)-4-(4-chlorophenyl)-3- methylbutane was converted to the Diastereomer ⁇ of the title compound following the same procedure as described for Diastereomer ⁇ .
  • Diastereomer ⁇ of 2-azido-3-(3-bromophenyl)-4-(4-chlorophenyl)-3- methylbutane was converted to Diastereomer ⁇ of the title compound following the same procedure as described for Diastereomer ⁇ .
  • Step B N-r4-(4-Chlorophenyl)-3-cvano-3-phenyl-2-butylidenel-2- methylpropane-(S)-sulfinamide.
  • Step C N- ⁇ r3-(4-Chlorophenyl)-2-cyano-2-phen yl- 1 -methyllpropyl ) -2- methylpropane-(S)-sulfinamide
  • N-[4-(4-chlorophenyl)-3-cyano-3-phenyl-2-butylidene]-2- methylpropane-(S)-sulfinamide (0.50 g, 1.3 mmol) in methanol (25 mL) at 0°C was added sodium borohydride (0.075 g, 1.9 mmol). After stirring for 15 min, the reaction was quenched by addition of saturated aqueous ammonium chloride (25 mL).
  • Step D N-( r3-(4-Chlorophenyl)-2-cvano-2-phenyl-l-methylpropyl1amine ⁇ hydrochloride salt N- ⁇ [3-(4-Chlorophenyl)-2-cyano-2-phenyl-l-methyl]propyl ⁇ -2-mefhylpropane-(S)- sulfinamide (0.55 g, 1.4 mmol) in methanol (20 mL) was added 4 M hydrogen chloride in dioxane (25 mL). After stirring for 30 min, the mixture was concentrated to dryness to give the title compound as a mixture of diastereomers ( ⁇ and ⁇ ). LC- MS: m/e 285 (M + H) + (Major diastereomer: 2.0; Minor diastereomer: 2.1 min).
  • Step B 3-(4-Chlorophenyl)-2-(3-bromophenyl)-l-[(N-butoxycarbonyl)amino-
  • Step C N-l [3-(4-Chlorophenyl)-2-(3-bromophenyl)-2-hydroxylpropyl ⁇ amine hydrochloride
  • 3-(4-chlorophenyl)-2-(3-bromophenyl)-l-[(N-butoxycarbonyl)amino- 2-hydroxy]propane (0.38 g, 0.86 mmol) in ethyl acetate (10 mL) was added 4 M hydrogen chloride in dioxane (20 mL). After stirring for 1 h, the mixture was concentrated to dryness to give the title compound.
  • Step A 3-(3-Bromophenyl)-2(S)-r(N-butoxycarbonyl)amino-4-(4- chlorophenyl)-3-hydroxyl butane
  • Step B 3-(3-Bromophenyl)-2(S)-[(N-butoxycarbonyl)amino-4-(4- chlorophenyl)-3-fluoro] butane
  • 3-(3-bromophenyl)-2(S)-[(N-butoxycarbonyl)amino-4-(4- chlorophenyl)-3-hydroxy] butane 2.0 g, 4.4 mmol
  • Step C N-U3-(4-Chlorophenyl)-2-(3-bromophenyl)-2-fluoro-l(S)- methyllpropyl ) amine hydrochloride
  • 3-(3-bromophenyl)-2(S)-[(N-butoxycarbonyl)amino-4-(4- chlorophenyl)-3-fluoro] butane (0.16 g, 0.35 mmol) in ethyl acetate (1 mL) was added 4 M hydrogen chloride in dioxane (4 mL). After stirring for 2 h, the mixture was concentrated to dryness to give the title compound.
  • Diastereomer ⁇ LC-MS: calculated for C21H21N 287, observed m/e 288 (M + H) + (2.3 min).
  • Diastereomer ⁇ LC-MS: calculated for C16H18CIN 259, observed m/e 260 (M + H) + (2.1 min).
  • Step A 4-(4-Cvanophenyl)-3-phenyl-2-butanone.
  • Step A (4-(4-cyanophenyl)-3-phenyl-2-butanone) (1.0 g, 4.0 mmol) was converted to the title compound following the procedure described in Reference Example 2, Steps E-I.
  • Step B 3-(2,4-Dichlorophenyl)-2-(4-chlorophenyl)propanol.
  • Step C 3-(2,4-Dichlorophenyl)-2-(4-chorophenyl)propanal.
  • Step E ⁇ -r3-(2,4-Dichlorophenyl)-2-(4-chorophenyl)-l-methylpropyn-2- methylpropanesulfinamide (3 isomers).
  • Step B Methyl 3,3-Bis(4-chlorophenyl)propionate
  • MeOH (20 mL) and 2 M aqueous hydrochloric acid (1 mL) was degassed and filled with hydrogen with a balloon.
  • the reaction mixture was filtered through CELITE diatomaceous earth, and the filtrate was concentrated to dryness. The residue was dissolved in 50 mL ether and was concentrated with 20 g silica gel.
  • Step C 3,3-Bis(4-chlorophenyl)propionic Acid
  • Step D N-r2,2-Bis(4-chlorophenyl)ethyl1allylcarbamate.
  • Step E 2,2-Bis(4-chlorophenyl)ethylamine hydrochloride salt.
  • N-[2,2-bis(4-chlorophenyl)ethyl]allylcarbamate 0.26 g, 0.73 mmol
  • tetrakis (triphenylphosphine)palladium 85 mg, 0.073 mmol
  • triphenylsilane 0.18 mL, l.lmmol
  • Step B 2-Amino-3-(4-chlorophenylthio)-3-(4-chlorophenyl)propane hydrochloride salt (two diastereomers)
  • the product of Step A methyl 2-(4-chlorophenylthio)-2-(4-chlorophenyl)acetate) (1.1 g, 3.0 mmol) was converted to the title compound following the procedures described in Reference Example 5, Steps B-E.
  • Step B To a solution of 3,4-bis(4-chlorophenyl)-2-methyl-2-butanol (Step B, 1.4 g, 4.5 mmol) and chloroacetonitrile (0.57 mL, 9.1 mmol) in acetic acid (0.7 mL) at -10°C was added concentrated sulfuric acid (0.31 mL, 14 mmol). After stirring at -10°C for 15 min and room temperature for 2 h, the reaction mixture was poured onto ice (20 g), and the product was extracted with EtOAc (3 x 20 mL).
  • Step B N-r3-(4-Chlorophenyl)-2-(3-cvanophenyl)-l-methylpropyl1amine hydrochloride (Diastereomer ⁇ )
  • Step B 2-(N-tert-Butoxycarbonyl)amino-3-(3-chlorophenyl)-4-(4- chlorophenvDbutane
  • 2-(N-tert-butoxycarbonyl)amino-4-(4-chlorophenyl)-3-(3- trimethylstanylphenyl)butane (0.55 g, 1.0 mmol) in 5 mL CH2CI2 at 0°C was added tert-butoxychloride (freshly prepared, 0.20 mL, 1.1 mmol). The reaction was allowed to warm to room temperature over 2 h, and the resulting mixture was concentrated with 2 g silica gel.
  • Step C N-[2-(3-Chloroophenyl)-3-(4-chlorophenyl)-l-methylpropyl]amine hydrochloride (Diastereomer ⁇ )
  • Step B N-r2-(3-Bromophenyl)-3-(4-chlorophenyl)-l-methylpropyllamine hydrochloride and N-r3-(4-chlorophenyl)-2-(3-iodophenyl)-l-methylpropyl]amine hydrochloride (1:1 mixture) (Diastereomer ⁇ )
  • DL-4-Chlorophenylalanine methyl ester (5.0 g, 23.36 mmol) was dissolved in 120 mL chloroform and placed into an oven-dried 3-neck flask equipped with a condenser and an addition funnel. Glacial acetic acid (0.267 mL, 4.672 mmol) was added. Finally, isoamylnitrite (3.8 mL, 28 mmol) was added dropwise while slowly bringing the reaction to reflux (73°C). The reaction was refluxed for 30 minutes and then cooled to 0°C. The reaction mixture was washed with cold 1 N sulfuric acid solution, cold water, cold saturated aqueous sodium bicarbonate solution, and then cold water again.
  • Step B Methyl 3-(4-chlorophenyl)-2-cyclobutylmethoxypropanoate.
  • methyl-2-diazo-3-(4- chlorophenyl)propanoate obtained from Step A
  • 1.05 mL 5 eq; 11.1 mmol
  • Rh2(OAc)4 catalyst 10 mg (1 mole %) of Rh2(OAc)4 catalyst.
  • the tube was sealed and heated to 90°C for 1.5 h.
  • Methyl magnesium bromide (1.4 mL 3M solution in ether) was added to the solution dropwise. The reaction was allowed to warm to room temperature. After 4 h the TLC indicated a complete reaction. The reaction was quenched with enough 10% citric acid to bring the pH of the solution to approximately 3. The aqueous layer was extract with ether. The combined organics were washed with water and then dried over MgSO4. The solvents were evaporated under reduced pressure and the crude material was purified by flash chromatography

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Addiction (AREA)
  • Psychiatry (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Vascular Medicine (AREA)
  • Child & Adolescent Psychology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Psychology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Nutrition Science (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Selon la présente invention, les nouveaux composés de formule structurale (I) sont des antagonistes et/ou des agonistes inverses du récepteur cannabinoïde 1 (CB1) et sont utiles dans le traitement, la prévention et la suppression de maladies induites par le récepteur CB1. Les composés selon la présente invention sont utiles en tant que médicaments psychotropes pour traiter la psychose, les déficiences de la mémoire, les troubles cognitifs, la migraine, la neuropathie, les troubles neuro-inflammatoires tels que la sclérose en plaques et le syndrome de Guillain-Barré, les séquelles inflammatoires de l'encéphalite virale, les accidents vasculaires cérébraux et le traumatisme crânien, les troubles de l'anxiété, le stress, l'épilepsie, la maladie de Parkinson, les troubles du déplacement et la schizophrénie. Lesdits composés sont également utilisés pour traiter les troubles liés à l'abus de substances psychoactives, pour traiter l'obésité ou les troubles de l'alimentation, ainsi que pour traiter l'asthme, la constipation, la pseudo-obstruction intestinale chronique et la cirrhose du foie.
EP03711667A 2002-03-26 2003-03-21 Amides spirocycliques en tant que modulateurs du recepteur cannabinoide Withdrawn EP1490043A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US36765502P 2002-03-26 2002-03-26
US367655P 2002-03-26
PCT/US2003/008722 WO2003082190A2 (fr) 2002-03-26 2003-03-21 Amides spirocycliques en tant que modulateurs du recepteur cannabinoide

Publications (2)

Publication Number Publication Date
EP1490043A2 true EP1490043A2 (fr) 2004-12-29
EP1490043A4 EP1490043A4 (fr) 2007-05-30

Family

ID=28675381

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03711667A Withdrawn EP1490043A4 (fr) 2002-03-26 2003-03-21 Amides spirocycliques en tant que modulateurs du recepteur cannabinoide

Country Status (6)

Country Link
US (1) US7423067B2 (fr)
EP (1) EP1490043A4 (fr)
JP (1) JP2005528366A (fr)
AU (1) AU2003215024B2 (fr)
CA (1) CA2479618A1 (fr)
WO (1) WO2003082190A2 (fr)

Families Citing this family (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200303304A (en) 2002-02-18 2003-09-01 Astrazeneca Ab Chemical compounds
EP1499306A4 (fr) 2002-04-12 2007-03-28 Merck & Co Inc Amides bicycliques
ATE375349T1 (de) 2002-08-02 2007-10-15 Merck & Co Inc Substituierte furo(2,3-b)pyridin derivate
US7129239B2 (en) 2002-10-28 2006-10-31 Pfizer Inc. Purine compounds and uses thereof
US7247628B2 (en) 2002-12-12 2007-07-24 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
EP1575901B1 (fr) * 2002-12-19 2012-10-10 Merck Sharp & Dohme Corp. Amides substitues
US7176210B2 (en) 2003-02-10 2007-02-13 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7268133B2 (en) 2003-04-23 2007-09-11 Pfizer, Inc. Patent Department Cannabinoid receptor ligands and uses thereof
US7141669B2 (en) 2003-04-23 2006-11-28 Pfizer Inc. Cannabiniod receptor ligands and uses thereof
US7145012B2 (en) 2003-04-23 2006-12-05 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7232823B2 (en) 2003-06-09 2007-06-19 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
CN1956949A (zh) * 2003-09-18 2007-05-02 默克公司 取代的磺酰胺
AU2004287849A1 (en) * 2003-10-30 2005-05-19 Merck Sharp & Dohme Corp. Aralkyl amines as cannabinoid receptor modulators
ATE478856T1 (de) 2004-01-28 2010-09-15 Hoffmann La Roche Spirobenzodioxole und deren verwendung als cb1- antagonisten
SE0400208D0 (sv) 2004-02-02 2004-02-02 Astrazeneca Ab Chemical compounds
TW200602314A (en) 2004-05-28 2006-01-16 Tanabe Seiyaku Co A novel pyrrolidine compound and a process for preparing the same
DE602005024430D1 (de) 2004-11-09 2010-12-09 Hoffmann La Roche Dibenzosuberon-derivate
GB0425248D0 (en) 2004-11-16 2004-12-15 Gw Pharma Ltd New use for cannabinoid
KR20070089151A (ko) 2004-11-16 2007-08-30 지더블유 파마 리미티드 카나비노이드의 새로운 용도
PA8660701A1 (es) 2005-02-04 2006-09-22 Pfizer Prod Inc Agonistas de pyy y sus usos
MX2007011498A (es) 2005-03-17 2007-10-11 Pfizer Derivados de n-(n-sulfonilaminometil)ciclopropanocarboxamida utiles para el tratamiento de dolor.
NZ564759A (en) 2005-06-30 2011-08-26 Prosidion Ltd GPCR agonists
US20090203750A1 (en) * 2005-08-24 2009-08-13 Alan Kozikowski 5-HT2C Receptor Agonists as Anorectic Agents
CA2651777A1 (fr) * 2006-05-15 2007-11-29 Merck & Co., Inc. Promedicaments d'alcool tertiaire
KR20090064478A (ko) 2006-11-13 2009-06-18 화이자 프로덕츠 인크. 디아릴, 디피리디닐 및 아릴-피리디닐 유도체, 및 이들의 용도
BRPI0806312A2 (pt) 2007-01-04 2011-09-06 Prosidion Ltd agonistas cgpr piperidina
GB0700122D0 (en) 2007-01-04 2007-02-14 Prosidion Ltd GPCR agonists
CL2008000018A1 (es) 2007-01-04 2008-08-01 Prosidion Ltd Compuestos derivados de heterociclos de nitrogeno y oxigeno, agonistas de gpcr; composicion farmaceutica que comprende a dicho compuesto; y uso del compuesto para el tratamiento de la obesidad, diabetes, sindrome metabolico, hiperlipidemia, toleranci
AR064736A1 (es) 2007-01-04 2009-04-22 Prosidion Ltd Agonistas de gpcr
ES2373181T3 (es) 2007-01-04 2012-02-01 Prosidion Ltd Agonistas de gpcr de piperidina.
GB0720389D0 (en) 2007-10-18 2008-11-12 Prosidion Ltd G-Protein Coupled Receptor Agonists
GB0720390D0 (en) 2007-10-18 2007-11-28 Prosidion Ltd G-Protein coupled receptor agonists
JP5492092B2 (ja) * 2007-11-07 2014-05-14 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃｂ２受容体を調節する化合物
AU2008329775A1 (en) 2007-11-30 2009-06-04 Biotie Therapies Gmbh Aryl and heteroaryl fused imidazo[1,5-a]pyrazines as inhibitors of phosphodiesterase 10
US20090270394A1 (en) * 2008-04-28 2009-10-29 Galemmo Jr Robert Cyclylamine derivatives as calcium channel blockers
CA2743489A1 (fr) 2008-11-17 2010-05-20 Merck Sharp & Dohme Corp. Amines bicycliques substituees pour le traitement du diabete
WO2010138833A1 (fr) 2009-05-29 2010-12-02 Wyeth Imidazo[1,5-a]quinoxalines substituées en tant qu'inhibiteurs de la phosphodiestérase 10
WO2010147791A1 (fr) * 2009-06-16 2010-12-23 Boehringer Ingelheim International Gmbh Dérivés d'azétidine 2-carboxamide qui modulent le récepteur cb2
CA2768577A1 (fr) 2009-07-23 2011-01-27 Schering Corporation Composes d?oxazepine benzofusionnes en tant qu?inhibiteurs de la coenzyme-stearoyle a delta-9 desaturase
WO2011011506A1 (fr) 2009-07-23 2011-01-27 Schering Corporation Composés oxazépine spirocyclique en tant qu'inhibiteurs de la stéaroyl-coenzyme a delta-9 désaturase
WO2011037771A1 (fr) * 2009-09-23 2011-03-31 Merck Sharp & Dohme Corp. Dérivé de diarylméthylamide présentant une activité d'antagoniste des récepteurs de l'hormone de mélano-concentration
EP2563764B1 (fr) 2010-04-26 2015-02-25 Merck Sharp & Dohme Corp. Nouveaux inhibiteurs de spiropipéridine prolylcarboxypeptidase
US9365539B2 (en) 2010-05-11 2016-06-14 Merck Sharp & Dohme Corp. Prolylcarboxypeptidase inhibitors
JP2013528172A (ja) 2010-05-21 2013-07-08 ファイザー・インク ２−フェニルベンゾイルアミド
EP2579873A4 (fr) 2010-06-11 2013-11-27 Merck Sharp & Dohme Nouveaux inhibiteurs de prolylcarboxypeptidase
EP2670731B1 (fr) * 2011-02-02 2016-05-25 Bionomics Limited Modulateurs allostériques positifs du récepteur nicotinique à l'acétylcholine -7 et leurs utilisations
US20130345392A1 (en) 2011-03-04 2013-12-26 Pfizer Inc Edn3-like peptides and uses thereof
CA2894126A1 (fr) 2012-12-21 2014-06-26 Epizyme, Inc. Inhibiteurs de prmt5 et leurs utilisations
EP3406607A1 (fr) 2012-12-21 2018-11-28 Epizyme, Inc. Inhibiteurs prmt5 contenant de la dihydro- ou tétrahydroisoquinoline et leurs utilisations
EP2935247B1 (fr) 2012-12-21 2019-08-28 Epizyme, Inc. Inhibiteurs de prmt5 et leurs utilisations
KR102173874B1 (ko) 2012-12-21 2020-11-05 에피자임, 인코포레이티드 테트라하이드로- 및 디하이드로-이소퀴놀린 prmt5 억제제 및 이의 용도
WO2014100716A1 (fr) 2012-12-21 2014-06-26 Epizyme, Inc. Inhibiteurs de prmt5 et leurs utilisations
CA2953572A1 (fr) 2014-08-04 2016-02-11 Epizyme, Inc. Inhibiteurs de prmt5 et leurs utilisations
MD3433234T2 (ro) 2016-03-22 2022-02-28 Merck Sharp & Dohme Modulatori alosterici ai receptorilor nicotinici de acetilcolină
US20200022945A1 (en) * 2018-07-18 2020-01-23 Contango Labs Inc. D/B/A Anewsha Rapidly dissolving pharmaceutical compositions and method of manufacturing

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0656354A1 (fr) * 1993-12-02 1995-06-07 Sanofi N-pipéridino-3-pyrazolecarboxamide substitué
WO1996033159A1 (fr) * 1995-04-21 1996-10-24 Abbott Laboratories Derives de cyclobutane utilises comme inhibiteurs de la synthase squalene et de la proteine farnesyltransferase
JPH1180124A (ja) * 1997-07-11 1999-03-26 Japan Tobacco Inc キノリン化合物及びその医薬用途

Family Cites Families (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3222395A (en) * 1965-12-07 Maleamic ackd derivatives
US4150052A (en) * 1971-02-04 1979-04-17 Wilkinson Sword Limited N-substituted paramenthane carboxamides
US5081122A (en) * 1990-03-05 1992-01-14 Sterling Drug Inc. Antiglaucoma compositions containing 4-arylcarbonyl-1-(4-morpholinyl)-lower-alkyl)-1H-indoles and method of use thereof
US5112820A (en) * 1990-03-05 1992-05-12 Sterling Drug Inc. Anti-glaucoma compositions containing 2- and 3-aminomethyl-6-arylcarbonyl- or 6-phenylthio-2,3-dihydropyrrolo-(1,2,3-de)-1,4-benzoxazines and method of use thereof
US4973587A (en) * 1990-03-08 1990-11-27 Sterling Drug Inc. 3-arylcarbonyl-1-aminoalkyl-1H-indole-containing antiglaucoma method
US5013837A (en) * 1990-03-08 1991-05-07 Sterling Drug Inc. 3-Arylcarbonyl-1H-indole-containing compounds
FR2692575B1 (fr) * 1992-06-23 1995-06-30 Sanofi Elf Nouveaux derives du pyrazole, procede pour leur preparation et compositions pharmaceutiques les contenant.
US5358939A (en) * 1992-06-25 1994-10-25 Rohm And Haas Company Fungicidal 2-aryl-2,2-disubstituted ethyl-1,2,4-triazoles
JPH07138214A (ja) * 1993-02-12 1995-05-30 Banyu Pharmaceut Co Ltd 置換アミド酸誘導体
US5292736A (en) * 1993-02-26 1994-03-08 Sterling Winthrop Inc. Morpholinoalkylindenes as antiglaucoma agents
FR2714057B1 (fr) 1993-12-17 1996-03-08 Sanofi Elf Nouveaux dérivés du 3-pyrazolecarboxamide, procédé pour leur préparation et compositions pharmaceutiques les contenant.
US5532237A (en) * 1995-02-15 1996-07-02 Merck Frosst Canada, Inc. Indole derivatives with affinity for the cannabinoid receptor
FR2741621B1 (fr) * 1995-11-23 1998-02-13 Sanofi Sa Nouveaux derives de pyrazole, procede pour leur preparation et compositions pharmaceutiques en contenant
CA2245586A1 (fr) 1996-02-06 1997-08-14 Japan Tobacco Inc. Composes chimiques et utilisation pharmaceutique
WO1998031227A1 (fr) 1997-01-21 1998-07-23 Smithkline Beecham Corporation Nouveaux modulateurs de recepteurs de cannabinoides
FR2758723B1 (fr) * 1997-01-28 1999-04-23 Sanofi Sa Utilisation des antagonistes des recepteurs aux cannabinoides centraux pour la preparation de medicaments
WO1998033765A1 (fr) 1997-02-04 1998-08-06 E.I. Du Pont De Nemours And Company Carboxamides fongicides
TR199902012T2 (xx) 1997-02-21 2000-01-21 Bayer Aktiengesellschaft Arils�lfonamidler ve analoglar�
US5948777A (en) 1997-03-18 1999-09-07 Smithkline Beecham Corporation Cannabinoid receptor agonists
AU8127998A (en) 1997-07-11 1999-02-08 Japan Tobacco Inc. Quinoline compounds and medicinal uses thereof
EP0911319A1 (fr) 1997-09-01 1999-04-28 Roche Diagnostics GmbH Inhibiteurs de la metalloproteinase matriciélle à base d'acide malonique
WO1999031048A1 (fr) 1997-12-15 1999-06-24 The Board Of Trustees Of The University Of Arkansas Amides fongicides
HN1998000027A (es) 1998-08-19 1999-06-02 Bayer Ip Gmbh Arilsulfonamidas y analagos
DE19837627A1 (de) 1998-08-19 2000-02-24 Bayer Ag Neue Aminosäureester von Arylsulfonamiden und Analoga
AU783223B2 (en) * 1999-07-28 2005-10-06 Ortho-Mcneil Pharmaceutical, Inc. Amine and amide derivatives as ligands for the neuropeptide Y Y5 receptor useful in the treatment of obesity and other disorders
FR2804604B1 (fr) 2000-02-09 2005-05-27 Sanofi Synthelabo Utilisation d'un antagoniste des recepteurs aux cannabinoides centraux pour la preparation de medicaments utiles pour faciliter l'arret de la consommation de tabac
FR2809621B1 (fr) 2000-05-12 2002-09-06 Sanofi Synthelabo Utilisation d'un antagoniste des recepteurs aux cannabinoides centraux pour la preparation de medicaments utiles comme antidiarrheiques
FR2814678B1 (fr) 2000-10-04 2002-12-20 Aventis Pharma Sa Association d'un antagoniste du recepteur cb1 et de sibutramine, les compositions pharmaceutiques les contenant et leur utilisation pour la traitement de l'obesite
US6538017B2 (en) 2001-03-09 2003-03-25 Ortho-Mcneil Pharmaceutical, Inc. Aminopyrrolidine sulfonamides as serine protease inhibitors
US6660756B2 (en) * 2001-03-28 2003-12-09 Pfizer Inc. N-phenpropylcyclopentyl-substituted glutaramide derivatives as inhibitors of neutral endopeptidase
US7420002B2 (en) 2001-06-11 2008-09-02 Xenoport Amino acid conjugates providing for sustained systemic concentrations of GABA analogues
EP1496838B1 (fr) * 2002-03-12 2010-11-03 Merck Sharp & Dohme Corp. Amides substitues
FR2837706A1 (fr) 2002-03-28 2003-10-03 Sanofi Synthelabo Utilisation d'un antagoniste des recepteurs aux cannabinoides cb1 pour la preparation de medicaments utiles pour traiter les dysfonctionnements sexuels et/ou ameliorer les performances sexuelles
US20050154202A1 (en) * 2002-04-05 2005-07-14 Hagmann William K. Substituted aryl amides
EP1499306A4 (fr) 2002-04-12 2007-03-28 Merck & Co Inc Amides bicycliques
EP1575901B1 (fr) * 2002-12-19 2012-10-10 Merck Sharp & Dohme Corp. Amides substitues

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0656354A1 (fr) * 1993-12-02 1995-06-07 Sanofi N-pipéridino-3-pyrazolecarboxamide substitué
WO1996033159A1 (fr) * 1995-04-21 1996-10-24 Abbott Laboratories Derives de cyclobutane utilises comme inhibiteurs de la synthase squalene et de la proteine farnesyltransferase
JPH1180124A (ja) * 1997-07-11 1999-03-26 Japan Tobacco Inc キノリン化合物及びその医薬用途

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
LACK L ET AL: "The intestinal action of benzmalecene: The relationship of its hypocholesterolemic effect to active transport of bile salts and other substances" JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, AMERICAN SOCIETY FOR PHARMACOLOGY AND EXPERIMENTAL THERAPEUTIC, US, vol. 139, 1963, pages 248-258, XP002966766 ISSN: 0022-3565 *
NICOLAUS B.J.R.: 'Symbiotic approach to drug design' DECISION MAKING IN DRUG RESEARCH 1983, pages 173 - 186, XP002197412 *
See also references of WO03082190A2 *

Also Published As

Publication number Publication date
US20050239828A1 (en) 2005-10-27
JP2005528366A (ja) 2005-09-22
CA2479618A1 (fr) 2003-10-09
US7423067B2 (en) 2008-09-09
EP1490043A4 (fr) 2007-05-30
AU2003215024B2 (en) 2008-02-21
WO2003082190A2 (fr) 2003-10-09
WO2003082190A3 (fr) 2004-02-19
AU2003215024A1 (en) 2003-10-13

Similar Documents

Publication Publication Date Title
US7423067B2 (en) Diphenyl cyclopentyl amides as cannabinoid-1 receptor inverse agonists
US6972295B2 (en) Substituted amides
AU2003223510B2 (en) Bicyclic amides
US20050154202A1 (en) Substituted aryl amides
US7405221B2 (en) Substituted pyrimidines
WO2003063781A2 (fr) Imidazoles substitues en tant que modulateurs du recepteur cannabinoide
AU2003218068B9 (en) Substituted amides
AU2007201276B2 (en) Substituted amides

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20041026

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

A4 Supplementary search report drawn up and despatched

Effective date: 20070502

RIC1 Information provided on ipc code assigned before grant

Ipc: C07D 213/61 20060101ALI20070424BHEP

Ipc: C07D 205/04 20060101ALI20070424BHEP

Ipc: C07C 237/24 20060101ALI20070424BHEP

Ipc: C07C 235/82 20060101ALI20070424BHEP

Ipc: C07C 235/40 20060101ALI20070424BHEP

Ipc: C07C 233/59 20060101AFI20070424BHEP

17Q First examination report despatched

Effective date: 20071220

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: MERCK SHARP & DOHME CORP.

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20111001